CN106478752A - A kind of preparation method of Telbivudine - Google Patents
A kind of preparation method of Telbivudine Download PDFInfo
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Abstract
The invention provides a kind of preparation method of Telbivudine, the method comprises the steps：1）Thymus pyrimidine and hexamethyldisilane amine are added to reaction in organic solvent；Described organic solvent includes dimethyl sulfoxide, N,N-dimethylformamide, N, one of N- diethylformamide；2）Add the chloro- 2- of (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) reaction of -4- methyl benzoic acid ester, add NaHCO3Solution, agitation and filtration, concentrating under reduced pressure is carried out to filtrate；3）Add alcohols solvent, add Sodium ethylate reaction, add cation exchange resin, insulated and stirred；Cooling is filtered, and filtrate being carried out concentrate until there being solid to separate out, carrying out crystallize, obtaining Telbivudine crude product.The present invention is low toxicity using reagent and raw material；Preparation process is simple, reaction condition are gentle, easily operated, raw material stable in physicochemical property；By-product is few, high income.
Description
Technical field
The invention belongs to the preparation field of Telbivudine and in particular to a kind of required reagent toxicity is low, technological operation easily and high income Telbivudine preparation method.
Background technology
Telbivudine is the treating hepatitis B medicine of Novartis's research and development, has virus replication evidence and has serum transaminase for treatment（ALT or AST）The persistently chronic hepatitis B of rising or hepatic tissue activeness pathological changes evidence.
Traditional preparation method, such as US6395716 and WO2001034618, not only step of preparation process is various and required expensive reagents are it is important that its yield is unsatisfactory.
In the prior art although having produced that step is shorter and the preferable technique of yield, but in its preparation process, often need pyridine to be used as reaction dissolvent, and need by the use of p-methyl benzene sulfonic chloride as raw material, such as CN200810121107.It is known that pyridine pollutes environment greatly and easily very much to the toxicity of human body, easily cause health problem and contamination accident, and when toluene sulfonyl chloride is used as raw material, production operation complexity difficulty, and easy rotten, impact product quality of degrading.
Therefore, under the premise of the simplicity ensureing technique and good yield, how to avoid the threat to health and environmental pollution for the preparation technology, and avoid the adverse effect being used toluene sulfonyl chloride to bring as raw material, become this area problem demanding prompt solution.
Content of the invention
Shortcoming for prior art, it is an object of the invention to provide a kind of preparation method of Telbivudine, the method not only can avoid the pyridine higher using toxicity, the complexity of preparation technology can also be reduced further and avoid the loss that feed degradation brings, the more importantly unexpected yield further increasing product, the method comprises the steps：
1）By thymus pyrimidine and hexamethyldisilane amine（HMDS）It is added in organic solvent, reacting by heating, described organic solvent includes dimethyl sulfoxide, DMF, N, one of N- diethylformamide；
2）To step 1）Gains add the chloro- 2- of (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) -4- methyl benzoic acid ester, reacts below 60 DEG C of temperature, adds saturation NaHCO afterwards3Solution, stirs and filters after being creamy white suspension shape to solution, take filtrate, filtrate is concentrated, preferably concentrating under reduced pressure；
3）To step 2）Gains add alcohols solvent, add Sodium ethylate, reacting by heating, add cation exchange resin, insulated and stirred；Cooling is filtered, and filtrate is carried out concentrate until there being solid to separate out；Cooling crystallize, obtains Telbivudine crude product after filtration, drying；
Also optional inclusion step 4）：Telbivudine crude product refined.
Chemical equation is as follows：
Wherein, step 4）：Refining of Telbivudine crude product, can complete purification step using the method for the refined Telbivudine crude product of prior art offer, it would however also be possible to employ the step 4 that the present invention provides）The process for purification of Telbivudine crude product is refined, and can obtain more excellent yield and purity.
Preferably, step 1）In, organic solvent is DMF.
Preferably, step 1）In, the addition of described hexamethyldisilane amine is 1.0-2.5 times of thymus pyrimidine weight, preferably 1.5～2 times, more preferably 1.8 times.Add by this raw material and can guarantee that reaction rate than both, be beneficial to the control of reaction yield and impurity again.
Preferably, step 1）In, reaction temperature is 60～130 DEG C, preferably 125～130 DEG C.
Preferably, step 2）In; (2S; 3R) the chloro- 2- of -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) addition of -4- methyl benzoic acid ester is 1.0-3.0 times of thymus pyrimidine weight, preferably 2.4-3.0 times.Add by this raw material and can guarantee that reaction rate than both, be beneficial to the control of reaction yield and impurity again.
Preferably, step 2）In, reaction temperature is less than 50 DEG C, preferably 20～40 DEG C, more preferably 25～35 DEG C；Reaction temperature is 25～35 DEG C, reacts and both can guarantee that reaction was smoothed out at a temperature of this, can preferably control by-product to generate again.
Preferably, step 3）In, the addition of Sodium ethylate is 0.1-0.3 times of thymus pyrimidine weight, preferably 0.16～0.18 times；Cation exchange resin addition is more than 2 times of thymus pyrimidine, preferably 2.5～8 times, more preferably 4～5 times.
Preferably, step 3）In, the reaction temperature of reacting by heating is more than 40 DEG C, and preferably 50～100 DEG C, further 65～75 DEG C, so that reactant liquor color is more shallow, products obtained therefrom outward appearance is more preferable for controlling reaction temperature.
According to this area it is generally understood that being the key realizing higher Telbivudine yield using pyridine and p-methyl benzene sulfonic chloride.The present inventor gropes through substantial amounts of experiment, discovery can utilize and include dimethyl sulfoxide, N, dinethylformamide, N, N- diethylformamide carries out the preparation of Telbivudine in interior high boiling organic solvent as reaction dissolvent and raw material of the present invention, and by the control of response parameter, the control of particularly above-mentioned key reaction parameter, such as reaction temperature and raw material addition ratio, not only achieve the purpose obtaining higher yields, also it is found surprisingly that gained yield ratio is also outstanding described in prior art simultaneously, and Control of Impurities effect projects.Therefore, present contribution to the art be not only only that solve prior art have to ensure yield using easily health and environment are worked the mischief and raw material is easy to degrade, operation is complicated technique technical barrier, more importantly further improves the yield of Telbivudine, the purity of Telbivudine meets use requirement simultaneously.
Preferably, step 1）In, the addition of described organic solvent is 5～10ml organic solvent/g thymus pyrimidine, and the amount of being preferably added to is 7ml organic solvent/g thymus pyrimidine.
Preferably, step 1）In, the response time is more than 18 hours, preferably more than 24 hours, more preferably 24-48 hour.
Preferably, step 2）In; described (2S; 3R) feed postition of the chloro- 2- of -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base 4- methyl benzoic acid ester is disposably to add or be dividedly in some parts, and preferably divides 4～6 batches of additions.It is dividedly in some parts and can control response speed very well, reduce impurity and generate.
Preferably, step 2）In, the response time is 6～12 hours.
Preferably, step 2）In, saturation NaHCO3Solution addition is 20-25 times of thymus pyrimidine weight.
Preferably, step 3）In, the addition of alcohols solvent is 12-15ml alcohols solvent/g thymus pyrimidine.
Preferably, step 3）In, described alcohols solvent includes one of methanol, dehydrated alcohol, isopropanol, n-butyl alcohol.In view of the cost of reagent, more preferably dehydrated alcohol.
Preferably, step 3）In, the response time of reacting by heating is more than 12 hours, preferably 12-18 hour.
Preferably, step 3）In, the mixing time of insulated and stirred is more than 30 minutes, preferably 30-60 minute.
Preferably, step 3）In, recrystallization temperature is -20～30 DEG C, preferably -5～0 DEG C.Carry out crystallize, high income at -5～0 DEG C, impurity is few.
Preferably, step 3）In, cooling is filtered into and is cooled to 56-66 DEG C and is filtered, and is further preferably cooled to 60 DEG C and is filtered.
Preferably, step 3）In, it is at 51-61 DEG C, filtrate to be concentrated that filtrate concentrates, and is preferable over 55 DEG C and filtrate is concentrated.
Preferably, step 4）In, described organic solvent includes one of ethyl acetate, n-butyl acetate, isopropyl acetate, preferably ethyl acetate；Described organic solvent is 1 with the w/v of Telbivudine crude product:3～10, preferably 1:4～6；Recrystallization temperature is -5～0 DEG C.Under such scheme, gained Telbivudine yield is higher, and purity is also more preferable.
The preparation method of the Telbivudine of the present invention, the yield of Telbivudine crude product can reach 83.8%, and purity reaches 98.60%, and the yield of the Telbivudine after refining can reach 94%, and purity can reach 99.50%, and total recovery is up to 78.7%.
Beneficial effects of the present invention：
1）The present invention is low toxicity using reagent and raw material, little to human body and environmental hazard；
2）Preparation process is simple of the present invention, reaction condition are gentle, easily operated, raw material stable in physicochemical property；
3）, in preparation process, by-product is few for the present invention, high income.
Brief description
Fig. 1 is the synthetic route chart of embodiment 1.
Specific embodiment
Below by embodiment, the present invention is specifically described; be necessary it is pointed out here that be that following examples are only intended to the present invention is further detailed; it is not intended that limiting the scope of the invention; the person skilled in the art in this field made according to foregoing invention content some nonessential improve and adjust, still fall within protection scope of the present invention.
Embodiment 1
1）：Weigh 10g thymus pyrimidine, under room temperature, add 50ml dimethyl sulfoxide, add 15g hexamethyldisilane amine（HMDS）, it is heated to 60～70 DEG C and reacts 28 hours, be stored in stand-by in reaction vessel after being down to 0-5 DEG C.
2）：Weigh the chloro- 2- of 24g (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) 4- methyl benzoic acid ester, it is divided into four parts, i.e. every part of 6g.The material weighing up was added every 10 minutes a, finish 20-25 DEG C of insulation and react 12 hours.Timing terminates to be slowly added to 200g saturation NaHCO3Solution, stirs and filters after being creamy white suspension shape to solution.70 DEG C of concentrating under reduced pressure of filtrate obtain final product the sticky mixture containing a large amount of compound B.
3）：Take 120ml methanol to add in step concentrate container, take 1.6g Sodium ethylate to add, stirring is warming up to 50-60 DEG C and reacts 18 hours, adds 40g cation exchange resin, insulated and stirred 30 minutes.It is cooled to 60 DEG C of filtrations, 55 DEG C of filtrate has been concentrated into solid and has separated out and stopped concentrating, crystallize of lowering the temperature.- 20～-15 DEG C of crystallizes of insulation 4 hours, filter, dry Telbivudine crude product 10.12g, yield：82.3%, purity is 98.76%.
4）：Take 1 weight portion Telbivudine crude product, add 30ml ethyl acetate, be warming up to return stirring 2 hours.Cooling crystallize, -20～-15 DEG C of insulation crystallizes 4 hours, filter, dry Telbivudine 9.42g, refined yield：93.0%, total recovery：76.4%, purity is 99.73%.
Experimental example 2
1）：Weigh 10g thymus pyrimidine, under room temperature, add 70ml dimethylformamide, add 18g hexamethyldisilane amine（HMDS）, it is heated to 80～90 DEG C and reacts 26 hours, be stored in stand-by in reaction vessel after being down to 0-5 DEG C.
2）：Weigh the chloro- 2- of 24g (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) -4- methyl benzoic acid ester, it is divided into four parts, i.e. every part of 6g.The material weighing up was added every 10 minutes a, finish 25-35 DEG C of insulation and react 10 hours.Timing terminates to be slowly added to 220g saturation NaHCO3Solution, stirs and filters after being creamy white suspension shape to solution.70 DEG C of concentrating under reduced pressure of filtrate obtain final product the sticky mixture containing a large amount of compound B.
3）：Take 130ml dehydrated alcohol to add in step concentrate container, take 1.7g Sodium ethylate to add, stirring is warming up to 65-75 DEG C and reacts 16 hours, adds 42g cation exchange resin, insulated and stirred 40 minutes.It is cooled to 60 DEG C of filtrations, 55 DEG C of filtrate has been concentrated into solid and has separated out and stopped concentrating, crystallize of lowering the temperature.- 5-0 DEG C of crystallize of insulation 4 hours, filters, dry Telbivudine crude product 10.30g, yield：83.8%, purity is 98.89%.
4）：Take 10g Telbivudine crude product, add 50ml ethyl acetate, be warming up to return stirring 2 hours.Cooling crystallize, -5-0 DEG C of insulation crystallize 4 hours, filters, dry Telbivudine 9.4g, refined yield：94.0%, total recovery：78.7%, purity is 99.81%.
Experimental example 3
1）：Weigh 10g thymus pyrimidine, under room temperature, add 80mlN ' N- diethyl base Methanamide, add 19g hexamethyldisilane amine（HMDS）, it is heated to 90～100 DEG C and reacts 26 hours, be stored in stand-by in reaction vessel after being down to 0-5 DEG C.
2）：Weigh the chloro- 2- of 24g (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base 4- methyl benzoic acid ester, be divided into four parts, i.e. every part of 6g.The material weighing up was added every 10 minutes a, finish 35-40 DEG C of insulation and react 8 hours.Timing terminates to add 230g saturation NaHCO3Solution, stirs and filters after being creamy white suspension shape to solution.70 DEG C of concentrating under reduced pressure of filtrate obtain final product the sticky mixture containing a large amount of compound B.
3）：Take 140ml isopropanol to add in step concentrate container, take 1.7g Sodium ethylate to add, stirring is warming up to 75-85 DEG C and reacts 14 hours, adds 45g cation exchange resin, insulated and stirred 50 minutes.It is cooled to 60 DEG C of filtrations, 55 DEG C of filtrate has been concentrated into solid and has separated out and stopped concentrating, crystallize of lowering the temperature.10-15 DEG C of crystallize of insulation 4 hours, filters, dry Telbivudine crude product 10.0g, yield：81.4%, purity is 98.80%.
4）：Take 10g Telbivudine crude product, add 70ml n-butyl acetate, be warming up to return stirring 2 hours.Cooling crystallize, 10-15 DEG C of insulation crystallize 4 hours, filters, dry Telbivudine 9.2g, refined yield：92.0%, total recovery：74.9%, purity is 99.86%.
Experimental example 4
1）：Weigh 10g thymus pyrimidine, under room temperature, add 100ml dimethylformamide, add 20g hexamethyldisilane amine（HMDS）, it is heated to 125～130 DEG C and reacts 24 hours, be stored in stand-by in reaction vessel after being down to 0-5 DEG C.
2）：Weigh the chloro- 2- of 24g (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base 4- methyl benzoic acid ester, be divided into four parts, i.e. every part of 6g.The material weighing up was added every 10 minutes a, finish 35-40 DEG C of insulation and react 6 hours.Timing terminates to be slowly added to 250g saturation NaHCO3Solution, stirs and filters after being creamy white suspension shape to solution.70 DEG C of concentrating under reduced pressure of filtrate obtain final product the sticky mixture containing a large amount of compound B.
3）：Take 150ml n-butyl alcohol to add in step concentrate container, take 1.8g Sodium ethylate to add, stirring is warming up to 90-100 DEG C and reacts 12 hours, adds 50g cation exchange resin, insulated and stirred 60 minutes.It is cooled to 60 DEG C of filtrations, 55 DEG C of filtrate has been concentrated into solid and has separated out and stopped concentrating, crystallize of lowering the temperature.25-30 DEG C of crystallize of insulation 4 hours, filters, dry Telbivudine crude product 10.3g, yield：83.8%, purity is 98.67%.
4）：Take 10g Telbivudine crude product, add 100ml isopropyl acetate, be warming up to return stirring 2 hours.Cooling crystallize, 25-30 DEG C of insulation crystallize 4 hours, filters, dry Telbivudine 9.3g, refined yield：93.0%, total recovery：77.9%, purity is 99.78%.
Embodiment 5
Except step 2）In; (2S; 3R) the chloro- 2- of -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) -4- methyl benzoic acid ester addition be 30g, every part be 7.5g outside, remaining is consistent with embodiment 1.Obtain Telbivudine crude product（10.26）, yield（83.4%）, purity is 98.58%；Refined yield（93.2%）, total recovery（77.6%）, purity is 99.84%.
Embodiment 6
Except step 2）In, the chloro- 2- of (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) -4- methyl benzoic acid ester addition be 28g, every part be 7g outside, remaining is consistent with embodiment 1.Obtain Telbivudine crude product 10.06g, yield 81.8%, purity is 98.66%；Refined yield 92.6%, total recovery 75.7%, purity is 99.74%.
Claims (10)
1. a kind of preparation method of Telbivudine is it is characterised in that methods described comprises the steps：
1）Thymus pyrimidine and hexamethyldisilane amine are added in organic solvent, reacting by heating, described organic solvent includes dimethyl sulfoxide, DMF, N, one of N- diethylformamide, preferably DMF；
2）To step 1）Gains add the chloro- 2- of (2S, 3R) -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) -4- methyl benzoic acid ester, reacts below 60 DEG C of temperature, adds saturation NaHCO afterwards3Solution, stirs and filters after being creamy white suspension shape to solution, take filtrate, filtrate is concentrated, preferably concentrating under reduced pressure；
3）To step 2）Gains add alcohols solvent, add Sodium ethylate, reacting by heating, add cation exchange resin, insulated and stirred；Cooling is filtered, and filtrate is carried out concentrate until there being solid to separate out；Cooling crystallize, obtains Telbivudine crude product after filtration, drying；
Also optionally include step 4）：Telbivudine crude product refined.
2. as claimed in claim 1 a kind of preparation method of Telbivudine it is characterised in that described step 4）The refined inclusion of Telbivudine crude product：To step 3）Gained Telbivudine crude product adds organic solvent, and temperature rising reflux stirs, and described organic solvent includes one of ethyl acetate, n-butyl acetate, isopropyl acetate；Then lower the temperature, carry out crystallize in -20～30 DEG C, filter, be dried to obtain Telbivudine.
3. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 1）In, the addition of described hexamethyldisilane amine is 1.0-2.5 times of thymus pyrimidine weight, preferably 1.5～2 times, more preferably 1.8 times.
4. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 1）In, reaction temperature is 60～130 DEG C, preferably 125-130 DEG C；Step 1）In, the response time is more than 18 hours, preferably more than 24 hours, more preferably 24-48 hour.
5. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 2）In; described (2S; 3R) the chloro- 2- of -5- (((4- methyl benzoyl) epoxide) methyl) oxolane -3- base) addition of -4- methyl benzoic acid ester is 1.0-3.0 times of thymus pyrimidine weight, preferably 2.4-3.0 times.
6. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 2）In, reaction temperature is less than 50 DEG C, preferably 20～40 DEG C, more preferably 25～35 DEG C；Step 2）In, the response time is 6～12 hours.
7. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 3）In, the addition of described Sodium ethylate is 0.1-0.3 times of thymus pyrimidine weight, preferably 0.16～0.18 times；Described cation exchange resin addition is more than 2 times of thymus pyrimidine, preferably 2.5～8 times, more preferably 4～5 times.
8. a kind of preparation method of Telbivudine according to claim 1 is it is characterised in that step 3）In, the reaction temperature of reacting by heating is more than 40 DEG C, preferably 50～100 DEG C, more preferably 65～75 DEG C；The response time of reacting by heating is more than 12 hours, preferably 12-18 hour；Step 3）In, the mixing time of insulated and stirred is more than 30 minutes, preferably 30-60 minute；Step 3）In, recrystallization temperature is -20～3 DEG C, preferably -5～0 DEG C.
9. a kind of preparation method of Telbivudine according to claim 2 is it is characterised in that step 4）In, described organic solvent includes one of ethyl acetate, n-butyl acetate, isopropyl acetate, preferably ethyl acetate；The weigh-volume of described organic solvent and Telbivudine crude product is than for 1:3～10, preferably 1:4～6；Recrystallization temperature is -5～0 DEG C.
10. a kind of preparation method of Telbivudine according to claim 1 and 2 is it is characterised in that step 1）In, the addition of described organic solvent is 5～10ml organic solvent/g thymus pyrimidine, and the amount of being preferably added to is 7ml organic solvent/g thymus pyrimidine.
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| EP0540742A1 (en) * | 1990-07-26 | 1993-05-12 | Shudo, Koichi, Prof. Dr. | Oligodeoxyribonucleotides |
| CN101415719A (en) * | 2003-03-20 | 2009-04-22 | 微生物化学及药品有限公司 | Methods of manufacture of 2 -deoxy-beta-L-nucleosides |
| CN100475831C (en) * | 2003-06-30 | 2009-04-08 | 诺瓦蒂斯有限公司 | Synthesis of beta-l-2'-deoxy nucleosides |
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